Upon encountering antigen, naive CD4+ T helper precursor (Thp) cells are differentiated into two distinct subsets, Type 1 T helper (Th1) and Type 2 T helper (Th2). Recently, a novel T cell subset, the Th17 cells, has also been identified and characterized These differentiated Th cells are defined both by their distinct functional abilities and by unique cytokine profiles. Specifically, Th1 cells produce interferon-gamma, interleukin (IL)-2, and tumor necrosis factor (TNF)-beta, which activate macrophages and are responsible for cell-mediated immunity and phagocyte-dependent protective responses. In contrast, Th2 cells are known to produce IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13, which are responsible for strong antibody production, eosinophil activation, and inhibition of several macrophage functions, thus providing phagocyte-independent protective responses. Th17 cells mainly produce IL-17A, IL-17F, IL-21, IL-22 & TNF and are required for host defense against extracellular pathogens and are critical mediators of autoimmunity. Accordingly, Th1, Th2, and Th17 cells are associated with different immunopathological responses.
In addition, the development of each type of Th cell is mediated by a different cytokine pathway. Specifically, it has been shown that IL-4 promotes Th2 differentiation and simultaneously blocks Th1 development. In contrast, IL-12, IL-18 and IFN-gamma are the cytokines critical for the development of Th1 cells. In murine, TGF-β & IL-6 are critical for the induction of Th17 cell differentiation, while in human, IL-1, IL-6 & IL-23 are important drivers of Th17 cell development. Accordingly, effective immunologic homeostasis relies on a continual balance between helper T cell activation and regulatory T cell (Treg) suppression.
Th1 cells are involved in the pathogenesis of a variety of organ-specific autoimmune disorders, Crohn's disease, Helicobacter pylori-induced peptic ulcer, acute kidney allograft rejection, and unexplained recurrent abortions. In contrast, allergen-specific Th2 responses are responsible for atopic disorders in genetically susceptible individuals. Moreover, Th2 responses against still unknown antigens predominate in Omenn's syndrome, idiopathic pulmonary fibrosis, and progressive systemic sclerosis. Th17 cells cause immunopathology in different models of autoimmunity, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease and psoriasis. IL-17 (the signature Th-17 cytokine) knock-out mice show marked resistance to inflammatory arthritis development. Joint destruction in the CIA model can be ameliorated by the administration of a neutralizing anti-IL-17 antibody.
There remains a high unmet medical need to develop new therapeutic treatments that are useful in treating the various conditions associated with imbalanced Th1/Th2 and Th17 cellular differentiation. For many of these conditions the currently available treatment options are inadequate. Accordingly, the Th1/Th2 and Th17 paradigm provides a rationale for the development of strategies for the therapy of allergic and autoimmune disorders.
Prostaglandins have been shown to modulate various phases of the immune response. The lipid mediator prostaglandin E2 (PGE2) is an eicasanoid that is well known to suppress CD4+ T cell activation through elevation of intracellular cAMP and inactivation of Ick. PGE2 has been also shown to play a role in regulating Th1 responses by suppression of interferon gamma (IFN-gamma) production and T cell proliferation. However PGE2 stimulation via the EP4 subtype of PGE2 receptor can also have the opposite effect, namely to promote Th1 differentiation (Prostaglandin E receptor subtypes EP2 and EP4 promote differentiation and expansion of Th1 and Th17 lymphocytes through different signaling modules, Nature Medicine, 2009, 15, 633-640) and IL-17 production in activated CD4+ cells. Prostaglandin E2 synergistically with interleukin-23 favors human Th17 expansion, Blood, 2008, 112, 3696-3703; Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling, J. Exp. Med. 2009, 206, 535-548; Prostaglandin E2 enhances Th17 response via modulation of IL-17 and IFN-γ production by memory CD4+ T cells, Eur. J. Immunol. 2009, 39, 1301-1312. Consistent with this, antagonism of EP4 with either a novel selective EP4 antagonist or a PGE2-neutralizing antibody suppresses Th1 differentiation, Th17 expansion, as well as IL-23 secretion by activated dendritic cells. Induction of Th1 differentiation by PGE2 is mediated by PI3K signaling whereas stimulation of IL-17 production requires cAMP signaling. In addition, administration of an EP4 antagonist to DBA/1 or C57BL/6 mice suppressed innate and adaptive immune responses, and suppressed disease in collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE) models, indicating that PGE2/EP4 signaling is critically involved in these autoimmune pathologies. These results suggest that suppression of PGE2/EP4 signaling may have therapeutic value in modifying inflammatory autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.